1. Field of the Invention
The present invention relates to heteroatom containing monocyclic and bicyclic compounds, pharmaceutical compositions containing these novel compounds, and to their use in therapy, in particular their use as nitric oxide synthase inhibitors.
2. Discussion of the Prior Art
It has been known since the early 1980""s that the vascular relaxation caused by acetylcholine is dependent on the presence of the vascular endothelium and this activity was ascribed to a labile humoral factor termed endothelium-derived relaxing factor (EDRF). The activity of nitric oxide (NO) as a vasodilator has been known for well over 100 years. In addition, NO is the active component of amylnitrite, glyceryltrinitrate and other nitrovasodilators. The recent identification of EDRF as NO has coincided with the discovery of a biochemical pathway by which NO is synthesized from the amino acid L-arginine by the enzyme NO synthase.
Nitric oxide is the endogenous stimulator of the soluble guanylate cyclase. In addition to endothelium-dependent relaxation, NO is involved in a number of biological actions including cytotoxicity of phagocytic cells and cell-to-cell communication in the central nervous system (see Moncada et al., Biochemical Pharmacology, 38, 1709-1715, 1989; Moncada et al., Pharmacological Reviews, 43, 109-142, 1991). Excess NO production appears to be involved in a number of pathological conditions, particularly conditions which involve systemic hypotension such as toxic shock, septic shock and therapy with certain cytokines (Kerwin et al., J. Medicinal Chemistry, 38, 4343-4362, 1995).
The synthesis of NO from L-arginine can be inhibited by the L-arginine analogue, L-N-monomethyl-arginine (L-NMMA) and the therapeutic use of L-NMMA for the treatment of toxic shock and other types of systemic hypotension has been proposed (WO 91/04024 and GB-A-2240041). The therapeutic use of certain other NO synthase inhibitors apart from L-NMMA for the same purpose has also been proposed in WO 91/04024 and in EP-A-0446699.
It has recently become apparent that there are at least three types of NO synthase as follows:
(i) a constitutive, Ca++/calmodulin dependent enzyme, located in the endothelium, that releases NO in response to receptor or physical stimulation.
(ii) a constitutive, Ca++/calmodulin dependent enzyme, located in the brain, that releases NO in response to receptor or physical stimulation.
(iii) a Ca++ independent enzyme which is induced after activation of vascular smooth muscle, macrophages, endothelial cells, and a number of other cells by endotoxin and cytokines. Once expressed this inducible NO synthase generates NO continuously for long periods.
The NO released by the two constitutive enzymes acts as a transduction mechanism underlying several physiological responses. The NO produced by the inducible enzyme is a cytotoxic molecule for tumor cells and invading microorganisms. It also appears that the adverse effects of excess NO production, in particular pathological vasodilation and tissue damage, may result largely from the effects of NO synthesized by the inducible NO synthase (Knowles and Moncada, Biochem J., 298, 249-258, 1994 Billiar et al., Annals of Surgery, 221, 339-349, 1995; Davies et al., 1995).
There is also a growing body of evidence that NO may be involved in the degeneration of cartilage which takes place in certain conditions such as arthritis and it is also known that NO synthesis is increased in rheumatoid arthritis and in osteoarthritis (McInnes et al., J. Exp. Med, 184, 1519-1524, 1996; Sakurai et al., J. Clin. Investig., 96, 2357-2363, 1995). Accordingly, conditions in which there is an advantage in inhibiting NO production from L-arginine include autoimmune and/or inflammatory conditions affecting the joints, for example arthritis, and also inflammatory bowel disease, cardivascular ischemia, diabetes, diabetic retinopathy, nephropathy, cardiomyopathy, congestive heart failure, myocarditis, atherosclerosis, migraine, reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, asthma, chronic obstructive pulmonary disease, bronchiectasis, herniated vertebral discs, obesity, psoriasis, rosacea, contact dermatitis, hyperalgesia (allodynia), cerebral ischemia [both focal ischemia, thrombotic stroke and global ischemia (secondary to cardiac arrest)], anxiety multiple sclerosis and other central nervous system disorders mediated by NO, for example Parkinson""s disease and Alzheimer""s disease, rhinitis, cancer therapy, and other disorders mediated by NO including opiate tolerance in patients needing protracted opiate analgesics, and benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behavior, for example, nicotine and eating disorders (Kerwin et al., J. Medicinal Chemistry, 38, 4343-4362, 1995; Knowles and Moncada, Biochem J., 298, 249-258, 1994; Davies et al., 1995; Pfeilschifter et al., Cell Biology International, 20, 51-58, 1996).
Further conditions in which there is an advantage in inhibiting NO production from L-arginine-include systemic hypotension associated with septic and/or toxic shock induced by a wide variety of agents; therapy with cytokines such as TNF, IL-1 and IL-2; and as an adjuvant to short term immunosuppression in transplant therapy (E. Kelly et al., J. Partent. Ent. Nutri., 19, 234-238, 1995; S. Moncada and E. Higgs, FASEB J., 9, 1319-1330, 1995; R. G. Kilbourn et al, Crit. Care Med., 23, 1018-1024, 1995).
More recently, NO has been identified as being a neurotransmitter in pain pathways of the spinal cord. The administration of NO synthase inhibitors in patients with cronic pain syndromes, and more specifically cronic tension-type headaches, has been shown to reduce the level of pain. (The Lancet, 353:256-257, 287-289)
Some of the NO synthase inhibitors proposed for therapeutic use so far, and in particular L-NMMA, are non-selective; they inhibit both the constitutive and the inducible NO synthases. Use of such a non-selective NO synthase inhibitor requires that great care be taken in order to avoid the potentially serious consequences of over-inhibition of the constitutive NO-synthase including hypertension and possible thrombosis and tissue damage. In particular, in the case of the therapeutic use of L-NMMA for the treatment of toxic shock it has been recommended that the patient must be subject to continuous blood pressure monitoring throughout the treatment. Thus, while non-selective NO synthase inhibitors have therapeutic utility provided that appropriate precautions are taken, NO synthase inhibitors which are selective in the sense that they inhibit the inducible NO synthase to a considerably greater extent than the constitutive isoforms of NO synthase would be of even greater therapeutic benefit and easier to use (S. Moncada and E. Higgs, FASEB J., 9, 1319-1330, 1995).
WO 96/35677, WO 96/33175, WO 96/15120, WO 95/11014, WO 95/11231 WO 95/25717, WO 95/24382, WO94/12165, WO94/14780, WO93/13055, EP0446699A1 and U.S. Pat. No. 5,132,453 disclose compounds that inhibit nitric oxide synthesis and preferentially inhibit the inducible isoform of nitric oxide synthase. The disclosures of which are hereby incorporated by reference in their entirety as if written herein.
In accordance with the present invention novel heterocyclic bicyclic derivatives are provided. These novel inhibitor compounds are represented by the following formula 
and salts, pharmaceutically acceptable esters, and prodrugs thereof, wherein:
R1 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, OR5, SR5, S(O)R5, S(O)2R5, C(O)R6, carboalkoxyalkyl, heterocyclyl, aromatic hydrocarbon and cycloalkyl, all of which may be optionally substituted by one or more of the groups selected from lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aryl, halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, P(R5)3, C(O)R5, OR5, SR5, S(O)R5, S(O)2R5, S(O)R7, S(O)2R7, SO2NR5R6, NR5SO2R6, CONR5R6,PO(OR5)(OR6), amidino, and guanidino, wherein all said substituents may be optionally substituted with one or more selected from the group consisting of halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, OR5, SR5, S(O)R5, S(O)2R5, S(O)R7, S(O)2R7, SO2NR5R6, PO(OR5)(OR6), C(O)R6, carboalkoxyalkyl, cyano, nitro, amidino, and guanidino, wherein R5 and R6 of SO2NR5R6 and NR5SO2R6 may be taken together to form a N-containing heterocycle, optionally substituted by one or more selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, and carboxyalkyl;
R1 may be 
wherein J is selected from the group consisting of O, S and NR;
R is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, heterocycle, aromatic hydrocarbon, alkylaryl, alkylheterocycle, all of which may be optionally substituted by one or more of alkyl, hydroxy, alkoxy, halogen, haloalkyl, cyano, amino, and nitro;
NR and R20 may optionally form a heterocycle;
R16 is selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, C(O)R6, carboalkoxyalkyl, CONR5R6, S(O)R5, S(O)2R5, SO2NR5R6, NR5SO2R6, PO(OR5)(OR6), amidino, and guanidino, wherein all said substituents may be optionally substituted with one or more of the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, C(O)R6, carboalkoxyalkyl, S(O)R8, S(O)2R8, S(O)R10, S(O)2R10, SO2NR8R9, NR8SO2, PO(OR8)(OR9), amidino, and guanidino;
R17 is selected from the group consisting of hydrogen, lower alkyl, hydroxyalkyl, alkoxyalkyl, haloalkyl, cycloalkyl, heterocycle, aromatic hydrocarbon, alkylaryl, and alkylheterocycle, all except hydrogen may be optionally substituted by one or more of alkyl, hydroxy, alkoxy, thiol, alkylthiol, halogen, haloalkyl, carboxyl, cyano, amino, and nitro;
R18 is selected from the group consisting of hydrogen, hydroxyl, R12, S(O)R11, SO2R11, CH2OC(O)xe2x80x94R11, and C(O)xe2x80x94R11 wherein C(O)xe2x80x94R11;
R18 and R20 may be taken together to form a 5- or 6-membered heterocyclic ring containing two or more heteroatoms which may be optionally substituted by one or more of R16;
R2 and L may be taken together to form a 3 to 9 membered alicyclic or heterocyclic ring which may be optionally substituted by one or more of R16;
R2 and R17 may be taken together to form a 4 to 9 membered alicyclic or heterocyclic ring which may be optionally substituted by one or more of R16;
R2 and R18 may be taken together to form a 6 to 9 membered heterocyclic ring which may be optionally substituted by one or more of R16;
L and R17 may be taken together to form a 3 to 9 membered alicyclic or heterocyclic ring which may be optionally substituted by one or more of R16;
L and R18 may be taken together to form a 4 to 9 membered alicyclic or heterocyclic ring which may be optionally substituted by one or more of R16;
R17 and R18 and may be taken together to form a 4 to 9 membered heterocyclic ring which may be optionally substituted by one or more of R16;
R17 and Q may be taken together to form a 3 to 9 membered alicyclic or heterocyclic ring which may be optionally substituted by one or more of R16;
R18 and Q may be taken together to form a 4 to 9 membered heterocyclic ring which may be optionally by one or more of R16;
R17 and R20 and may be taken together to form a 5 to 9 membered heterocyclic ring which may be optionally substituted by one or more of R16;
R19 is hydrogen, R11, or C(O)xe2x80x94R11;
R11 is selected from the group consisting of hydrogen, hydroxyl, alkenyl, alkynyl, heterocyclyl, aromatic hydrocarbon, cycloalkyl, dihydropyridyl, alkyl, alkylthiol, alkoxy, amino, and cycloalkoxy, which may be optionally substituted with one or more of amino, carboxyl, carboxamide, thioalkyl, aromatic hydrocarbon, alkyl, alkylaryl, hydroxy, alkoxy, halogen, trifluoromethyl, nitro, cyano, amino, heterocyclyl, alkylheterocycle, and alkylthiol, which may be optionally substituted with one or more of hydroxy, amino, guanidino, iminoalkyl;
R12 is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycle, and aromatic hydrocarbon, all may be optionally substituted by one or more alkyl, hydroxy, alkoxy, halogen, trifluoromethyl, nitro, cyano, or amino groups;
R20 is selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, cycloalkenyl, aromatic hydrocarbon, heterocycle, alkylaryl, and alkylheterocycle, which may be optionally substituted by one or more of halogen, haloalkyl, cyano, nitro, xe2x80x94CO2R, and xe2x80x94COR;
R20 may also be selected from the group consisting of alkylhydroxy, alkylpolyhydroxy, alkyl(poly)oxyacyl, CH2C(xe2x95x90O)OR12, CH2C(xe2x95x90O)NHR12, CH2OC(xe2x95x90O)R12, and CH2OC(xe2x95x90O)VR12, wherein the CH2 may be optionally substituted by one or more of lower alkyl, cycloalkyl, heterocycle, aromatic hydrocarbon, amidino, guanidino, CO2H, amino, hydroxy, thiol, halogen, haloalkyl, cyano, and nitro;
V is selected from the group consisting of O, S, CH2, CHR12, C(R12)2, NH, and NR12;
R2, R3, R4 are independently selected from the group consisting of hydrogen, lower alkyl, lower alkenyl, lower alkynyl, aromatic hydrocarbon, heterocyclyl, C(O)R6, carboalkoxyalkyl, OR5, SR5, S(O)R5, S(O)2R5, S(O)R7, S(O)2R7, SO2NR5R6, NR5SO2R6, CONR5R6, PO(OR5)(OR6), halogen, nitro, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, alkylaminoaryl, acylamino, carboxyl, carboalkoxy, carboaryloxy, carboarylalkyloxy, cyano, aminocarbonylalkoxy, aminocarbonylamino, aminocarbonylaminoalkyl, carboxyaldehyde, and haloalkyl, wherein all said substituents may be optionally substituted by one or more selected from the group consisting of hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, C(O)R6, carboalkoxyalkyl, CONR5R6, NR5SO2R6, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano, nitro, C(O)NR5OR5, OR5, SR5, S(O)R5, S(O)2R5, S(O)R7, S(O)2R7, SO2NR5R6, PO(OR5)(OR6), amidino, and guanidino, wherein all said substitutions may be optionally substituted with one or more of the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, C(O)R6, carboalkoxyalkyl, S(O)R5, S(O)2R5, S(O)R7, S(O)2R7, SO2NR5R6, NR5SO2, PO(OR5)(OR6), amidino, and guanidino;
G is selected from the group consisting of NR5, O, S, SO, SO2, (CH2)p, and CHxe2x95x90CH, wherein p is 0 to 6;
A is selected from the group consisting of NR5, O, S, SO, SO2, (CH2)q, and CHxe2x95x90CH, q is 0 to 6;
B is selected from the group consisting of NR5, O, S, SO, SO2, (CH2)v, and CHxe2x95x90CH. v is 0 to 6;
R1 and R2 may optionally be taken together to form an alicyclic hydrocarbon, heterocyclyl or aromatic hydrocarbon and said optionally formed ring may be optionally substituted with one or more selected from the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano, nitro, C(O)R6, carboalkoxyalkyl, OR5, SR5, S(O)R5, S(O)2R5, S(O)R7, S(O)2R7, SO2NR5R6, PO(OR5)(OR6), amidino, and guanidino;
R2 and R3 may optionally be taken together to form an alicyclic hydrocarbon, heterocyclyl or aromatic hydrocarbon and said optionally formed ring may be optionally substituted with one or more selected from the group consisting of, amino, alkylamino, dialkylamino, aminoalkyl, dialkylaminoalkyl, arylamino, aminoaryl, alkylaminoaryl, acylamino, carboxy, carboxyalkyl, CONR5R6, NR5SO2R6, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, halogen, cyano, nitro, C(O)R6, carboalkoxyalkyl, OR5, SR5, S(O)R5, S(O)2R5, S(O)R7, S(O)2R7, SO2NR5R6, PO(OR5)(OR6), amidino, and guanidino, wherein all said substitutions may be optionally substituted with one or more of the group consisting of lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, hydroxy, lower alkoxy, aryloxy, thiol, lower thioalkoxy, halogen, cyano, nitro, C(O)R6, carboalkoxyalkyl, S(O)R5, S(O)2R5, S(O)R7, S(O)2R7, SO2NR5R6, NR5SO2, PO(OR5)(OR6), amidino, and guanidino.
L and Q are independently selected from the group consisting of lower alkylene, lower alkenylene, lower alkynylene, heterocyclyl, cycloalkyl, aromatic hydrocarbon, and xe2x80x94(CH2)mxe2x80x94Mxe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)kxe2x80x94, wherein all said substituents may optionally be substituted by one or more lower alkyl, lower alkenyl, lower alkynyl, C(O)R6, carboalkoxyalkyl, OR5, SR5, S(O)R5, S(O)2R5, SO2NR5R6, NR5SO2R6, C(O)R5, heterocyclyl, halogen, nitro, cyano, haloalkyl, cycloalkyl, heterocyclyl, aromatic hydrocarbon, lactonyl, lactamyl, amidino, isourea, isothiourea, guanidino, and substituted guanidino;
k is 0 to 8;
m is 0 to 7;
n is 0 to 5;
M is selected from the group consisting of cycloalkyl, heterocyclyl, aromatic hydrocarbon, O, S, SO, SO2, SO2NR5, NR5SO2, NR5, POOR5, PON(R5)2, POOR5NR5, NR5POOR5, C(O), C(O)O, Se, SeO, SeO2, C(O)NR13, and SiE2, wherein R13 is selected from the group consisting of hydrogen, lower alkyl, alkaryl, heterocyclyl, COR14, and CO2R14 wherein R14 is lower alkyl or aromatic hydrocarbon;
E is lower alkyl or aryl;
L and R2 may be taken together to form a lower alkylidene;
R5 is selected from the group consisting of hydrogen, halogen lower alkyl, aromatic hydrocarbon, and alkylaryl, wherein all said substituents may be optionally substituted by one or more carboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, lower alkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides, phosphonates, and sulfonates;
R6 is selected from the group consisting of hydrogen, lower alkyl, aromatic hydrocarbon and alkylaryl wherein all said substituents may be optionally substituted by one or more carboalkoxy, thiol, amino, hydroxyl, carboxyl, lower alkyl, lower alkenyl, lower alkynyl, halo, cyano, nitro, carboxyalkyl, carboxamides, phosphonates, and sulfonates;
R7 is selected from the group consisting of hydroxy, alkoxy, and aryloxyl;
X is selected from the group consisting of O, S, C(xe2x95x90O), C(xe2x95x90S), Cxe2x95x90C(R11)2, S(xe2x95x90O), SO2, and C(R11)2;
Y is a bond, or is selected from the group consisting of O, S, C(xe2x95x90O), C(xe2x95x90S), Cxe2x95x90C(R11)2, S(xe2x95x90O), SO2, and C(R11)2;
Z is selected from the group consisting of O, S, C(xe2x95x90O), C(xe2x95x90S), Cxe2x95x90C(R11)2, S(xe2x95x90O), SO2, and C(R11)2.
More preferred embodiments of the invention are shown in the claims.
In another broad aspect, the present invention is directed to inhibiting nitric oxide synthesis in a subject in need of such inhibition or treatment by administering a compound of Formulas I and II which preferentially inhibits the inducible isoform of nitric oxide synthase over the constitutive isoform of nitric oxide synthase, in a nitric oxide synthesis inhibiting amount to such subject.
The invention further relates to a pharmaceutical composition comprising a compound from Formulas I and II.
Conditions in which there is an advantage in inhibiting NO production from L-arginine in disorders mediated by nitric oxide include amongst others, disorders involving systemic hypotension associated with septic and/or toxic shock induced by a wide variety of agents; therapy with cytokines such as TNF, IL-1 and IL-2; and as an adjuvant to short term immunosuppression in transplant therapy. Further conditions in which there is an advantage in inhibiting NO production from L-arginine include autoimmune diseases and/or inflammatory conditions such as those affecting the joints, for example arthritis or inflammatory bowel disease, cardiovascular ischemia, diabetes, congestive heart failure, myocarditis, artherosclerosis, migraine, reflux esophagitis, diarrhea, irritable bowel syndrome, cystic fibrosis, emphysema, hyperalgesia (allodynia) cerebral ischemia (both focal ischemia, thrombotic stroke and global ischemia, secondary to cardiac arrest) and other CNS disorder mediated by NO, including opiate tolerance in patients needing protracted opiate analgesics, benzodiazepine tolerance in patients taking benzodiazepines, and other addictive behaviors for example nicotine and eating disorder.
The present invention includes compounds of Formulas I and II in the form of salts, in particular acid addition salts. Suitable salts include those formed with both organic and inorganic acids. Such acid addition salts will normally be pharmaceutically acceptable although salts of non-pharmaceutically acceptable salts may be of utility in the preparation and purification of the compound in question. Thus, preferred salts include those formed from hydrochloric, hydrobromic, sulfuric, citric, tartaric, phosphoric, lactic, acetic, succinic, fumaric, maleic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, benzenesulfonic and the like. (See, for example, S. M. Berge et al., Pharmaceutical Salts, J. Pharm. Sci., 1977, 66, 1-19.) Salts of the compounds of Formula I can be made by reacting the appropriate compound in the form of the free base with the appropriate acid.
While it may be possible for the compounds of Formulas I and II to be administered as the raw chemical, it is preferable to present them as a pharmaceutical formulation. According to a further aspect, the present invention provides a pharmaceutical formulation comprising a compound of Formulas I and II or a pharmaceutically acceptable salt or solvate thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one or more other therapeutic ingredients. The carrier(s) must be xe2x80x9cacceptablexe2x80x9d in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The formulations include those suitable for oral, inhalation, parenteral (including subcutaneous, intradermal, intramuscular, intravenous and intraarticular), rectal and topical (including dermal, buccal, sublingual and intraocular) administration although the most suitable route may depend upon for example the condition and disorder of the recipient. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing into association a compound of Formulas I and II or a pharmaceutically acceptable salt or solvate thereof (xe2x80x9cactive ingredientxe2x80x9d) with the carrier which constitutes one or more accessory ingredients. In general, the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.
Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous liquid or a non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.
A tablet may be made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, lubricating, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein.
Formulations for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example, saline, water-for-injection, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described.
Formulations for rectal administration may be presented as a suppository with the usual carriers such as cocoa butter or polyethylene glycol.
Formulations for topical administration in the mouth, for example buccally or sublingually, include lozenges comprising the active ingredient in a flavored basis such as sucrose and acacia or tragacanth, and pastilles comprising the active ingredient in a basis such as gelatin and glycerin or sucrose and acacia.
Formulations for inhalation administration where the active ingredient is inhaled into the lungs either as a mist or co-administered with an inert carrier agent.
Preferred unit dosage formulations are those containing an effective dose, as hereinbelow recited, or an appropriate fraction thereof, of the active ingredient.
It should be understood that in addition to the ingredients particularly mentioned above, the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
The compounds of the invention may be administered orally or via injection at a dose of from 0.001 to 2500 mg/kg per day. The dose range for adult humans is generally from 0.005 mg to 10 g/day. Tablets or other forms of presentation provided in discrete units may conveniently contain an amount of compound of the invention which is effective at such dosage or as a multiple of the same, for instance, units containing 5 mg to 500 mg, usually around 10 mg to 200 mg.
The compounds of Formulas I and II are preferably administered orally or by injection (intravenous or subcutaneous). The precise amount of compound administered to a patient will be the responsibility of the attendant physician. However, the dose employed will depend on a number of factors, including the age and sex of the patient, the precise disorder being treated, and its severity. Also, the route of administration may vary depending on the condition and its severity.
The term xe2x80x9clower alkylxe2x80x9d, alone or in combination, means an acyclic alkyl radical containing from 1 to about 10, preferably from 1 to about 8 carbon atoms and more preferably 1 to about 6 carbon atoms. Examples of such radicals include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, iso-amyl, hexyl, octyl and the like.
The term xe2x80x9clower alkenylxe2x80x9d refers to an unsaturated acyclic hydrocarbon radical in so much as it contains at least one double bond. Such radicals containing from about 2 to about 10 carbon atoms, preferably from about 2 to about 8 carbon atoms and more preferably 2 to about 6 carbon atoms. Examples of suitable alkenyl radicals include propylenyl, buten-1-yl, isobutenyl, pentenylen-1-yl, 2-2-methylbuten-1-yl, 3-methylbuten-1-yl, hexen-1-yl, hepten-1-yl, and octen-1-yl, and the like.
The term xe2x80x9clower alkynylxe2x80x9d refers to an unsaturated acyclic hydrocarbon radical in so much as it contains one or more triple bonds, such radicals containing about 2 to about 10 carbon atoms, preferably having from about 2 to about 8 carbon atoms and more preferably having 2 to about 6 carbon atoms. Examples of suitable alkynyl radicals include ethynyl, propynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals and the like.
The term xe2x80x9calicyclic hydrocarbonxe2x80x9d or xe2x80x9ccycloalkylxe2x80x9d means a aliphatic radical in a ring with 3 to about 10 carbon atoms, and preferably from 3 to about 6 carbon atoms. Examples of suitable alicyclic radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl and the like.
The term xe2x80x9caromatic hydrocarbonxe2x80x9d means and unsaturated cyclic or plycyclic radical with 4 to about 16 carbon atoms, preferably 6 to about 12 carbon atoms, more preferably 6 to about 10 carbon atoms. Examples of suitable aromatic hydrocarbon radicals include phenyl, naphthyl, thienyl, furanyl, pyridinyl, (is)oxazoyl and the like.and the like.
The term xe2x80x9cDCMxe2x80x9d means dichloromethane.
The term xe2x80x9cDEADxe2x80x9d means diethyl azodicarboxylate.
The term xe2x80x9cDIBAL-Hxe2x80x9d means diisobutylaluminum hydride.
The term xe2x80x9cDMAPxe2x80x9d means dimethylaminopyridine.
The term xe2x80x9cDMSOxe2x80x9d means dimethylsulfoxide.
The term xe2x80x9cEDCxe2x80x9d means 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride.
The term xe2x80x9cheterocyclylxe2x80x9d means a saturated or unsaturated cyclic hydrocarbon radical including aromatic systems with 4 to about 10 carbon atoms, preferably about 5 to about 6; wherein 1 to about 4 carbon atoms are replaced by nitrogen, oxygen, sulfur, or carbonyl. The xe2x80x9cheterocyclic radicalxe2x80x9d may be fused to an aromatic hydrocarbon radical. Suitable examples include pyrrolyl, pyridinyl, pyrazolyl, triazolyl, pyrimidinyl, pyridazinyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, indolyl, thienyl, furanyl, tetrazolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolindinyl, 1,3-dioxolanyl, 2-imidazolinyl, imidazolidinyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolinyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, 2H-pyranyl, 4H-pyranyl, piperidinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyrazinyl, piperazinyl, triazinyl, 1,3,5-trithianyl, benzo(b)thiophenyl, benzimidazolyl, quinolinyl, and the like.
The term xe2x80x9cHOBTxe2x80x9d means N-hydroxybenzotriazole.
The term xe2x80x9clower alkoxyxe2x80x9d, alone or in combination, means an alkyl ether radical wherein the term alkyl is as defined above and most preferably containing 1 to about 4 carbon atoms. Examples of suitable alkyl ether radicals include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy and the like.
The term xe2x80x9clower thioalkoxyxe2x80x9d, alone or in combination, means an alkyl thioether radical wherein the term alkyl is as defined above and most preferably containing 1 to about 4 carbon atoms. Examples of suitable alkyl thioether radicals include thiomethoxy, thioethoxy, thio-n-propoxy, thio-i-propoxy, thio-n-butoxy, thio-iso-butoxy, thio-sec-butoxy, thio-tert-butoxy and the like.
The term xe2x80x9calkoxycarbonylxe2x80x9d as used herein means an alkoxy group, as defined above, having a carbonyl (Cxe2x95x90O) group attached.
The term xe2x80x9chalogenxe2x80x9d means fluorine, chlorine, bromine or iodine.
The term xe2x80x9cMCPBAxe2x80x9d means m-chloroperbenzoic acid.
The term xe2x80x9cNMMxe2x80x9d means N-methylmorpholine.
The term xe2x80x9cNMMOxe2x80x9d means 4-methylmorpholine N-oxide.
The term xe2x80x9cprodrugxe2x80x9d refers to a compound that is made more active in vivo.
The term xe2x80x9csulfinylxe2x80x9d means SO.
The term xe2x80x9csulfonylxe2x80x9d means SO2.
The term xe2x80x9cTEAxe2x80x9d means triethylamine.
The term xe2x80x9cTMSN3xe2x80x9d means azidotrimethylsilane.
As used herein, reference to xe2x80x9ctreatmentxe2x80x9d of a patient is intended to include prophylaxis.
All references, patents or applications, U.S. or foreign, cited in the application are hereby incorporated by reference as if written herein.
Compounds of the present invention can exist in geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis- and trans-geometric isomers, E- and Z-geometric isomers, R- and S-enantiomers, diastereomers, d-isomers, l-isomers, the racemic mixtures thereof and other mixtures thereof, as falling within the scope of the invention.
Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore, the following preferred specific embodiments are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever.
All experiments were performed under either dry nitrogen or argon. All solvents and reagents were used without further purification unless otherwise noted. The routine work-up of the reactions involved the addition of the reaction mixture to a mixture of either neutral, or acidic, or basic aqueous solutions and organic solvent. The aqueous layer was extracted n times (x) with the indicated organic solvent. The combined organic extracts were washed n times (x) with the indicated aqueous solutions, dried over anhydrous Na2SO4, filtered, concentrated in vacuo, and purified as indicated. Separations by column chromatography were achieved with conditions described by Still. (Still, W. C.; Kahn, M.; Mitra, A. Rapid Chromatograhic Technique for Preparative Separation with Moderate Resolution. J. Org. Chem., 1978, 43, 2923-2925.) The hydrochloride salts were made from 1N HCl, HCl in ethanol (EtOH), 2 N in MeOH, or 6 N HCl in dioxane. Thin layer chromatograms were run on 0.25 mm EM precoated plates of silica gel 60 F254. High performance liquid chromatograms (HPLC) were obtained from C-8 or C-18 reverse phase columns which were obtained from several vendors. Analytical samples were dried in an Abderhalden apparatus at either 56_C or 78_C. 1H NMR spectra were obtained from either General Electric QE-300 or Varian VXR 400 MHz spectrometer with tetramethylsilane as an internal standard. 13C NMR were obtained from a Varian spectrometer at 125.8 MHz with tetramethylsilane as an internal standard.
Disclosed are twenty two general synthetic processes useful in the preparation of the compounds of the present invention. 